CTNS – Juvenile Nephropathic Cystinosis

CTNS encodes cystinosin, a seven‐transmembrane lysosomal cystine exporter essential for intracellular cystine homeostasis. Biallelic pathogenic variants in CTNS lead to juvenile nephropathic cystinosis, characterized by progressive renal Fanconi syndrome and extrarenal complications such as photophobia and myopathy. The disease follows an autosomal recessive inheritance pattern, with onset typically in late childhood to adolescence (PMID:10556299).

Initial cohort analyses identified 23 distinct CTNS mutations in 25 individuals with infantile nephropathic cystinosis, including a common ~65 kb deletion encompassing exons 1–10 and a spectrum of novel alleles (PMID:10556299). Loss‐of‐function variants account for 12/25 infantile cases, while missense and in‐frame indels disrupting transmembrane domains underlie milder juvenile phenotypes. Segregation in multiple affected sib pairs further supports pathogenicity though precise counts are limited.

Functional assays of CTNS missense and in‐frame deletions demonstrate that 16/19 infantile‐associated variants abolish cystine transport, whereas juvenile‐onset alleles retain residual activity correlating with disease severity (PMID:15128704). Site‐directed promoter studies revealed Sp-1 motif mutations (c.-295G>C) that reduce CTNS transcription without affecting adjacent CARKL expression (PMID:11505338).

Advanced proteomic and cell‐biological work established that glycosylation‐deficient mutants (ΔITILELP) undergo accelerated lysosomal degradation and ER retention, contributing to variable phenotypes (PMID:28082515). Recent ERAD pathway studies detailed the role of HRD1, p97, and EDEMs in cystinosin(7Δ) turnover and demonstrated that chemical chaperones can rescue folding and reduce cystine accumulation by ~70% (PMID:37561577).

No conflicting data have disputed the CTNS–juvenile nephropathic cystinosis relationship. The totality of genetic and experimental evidence, spanning >140 alleles and two decades of research, establishes a definitive gene‐disease association. Diagnostic testing for CTNS variants informs prognosis based on residual transport, and emerging therapies target protein folding defects to restore function.

Key Take-home: CTNS molecular testing is critical for early diagnosis and tailored management of juvenile nephropathic cystinosis, and functional assays guide variant interpretation and therapeutic development.

References

• Human molecular genetics • 1999 • Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin. PMID:10556299
• American journal of human genetics • 2001 • The promoter of a lysosomal membrane transporter gene, CTNS, binds Sp-1, shares sequences with the promoter of an adjacent gene, CARKL, and causes cystinosis if mutated in a critical region. PMID:11505338
• Human molecular genetics • 2004 • Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. PMID:15128704
• Molecular & cellular proteomics : MCP • 2017 • Impact of Cystinosin Glycosylation on Protein Stability by Differential Dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC). PMID:28082515
• The Journal of clinical investigation • 2023 • ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine. PMID:37561577

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